Distribution of a novel CYP2C haplotype in Native American populations.

The CYP2C19 gene, located in the CYP2C cluster, encodes the major drug metabolism enzyme CYP2C19. This gene is highly polymorphic and no-function (CYP2C19*2 and CYP2C19*3), reduced function (CYP2C19*9) and increased function (CYP2C19*17) star alleles (haplotypes) are commonly used to predict CYP2C19 metabolic phenotypes. CYP2C19*17 and the genotype-predicted rapid (RM) and ultrarapid (UM) CYP2C19 metabolic phenotypes are absent or rare in several Native American populations. However, discordance between genotype-predicted and pharmacokinetically determined CYP2C19 phenotypes in Native American cohorts have been reported. Recently, a haplotype defined by rs2860840T and rs11188059G alleles in the CYP2C cluster has been shown to encode increased rate of metabolism of the CYP2C19 substrate escitalopram, to a similar extent as CYP2C19*17. We investigated the distribution of the CYP2C:TG haplotype and explored its potential impact on CYP2C19 metabolic activity in Native American populations. The study cohorts included individuals from the One Thousand Genomes Project AMR superpopulation (1 KG_AMR), the Human Genome Diversity Project (HGDP), and from indigenous populations living in Brazil (Kaingang and Guarani). The frequency range of the CYP2C:TG haplotype in the study cohorts, 0.469 to 0.598, is considerably higher than in all 1 KG superpopulations (range: 0.014-to 0.340). We suggest that the high frequency of the CYP2C:TG haplotype might contribute to the reported discordance between CYP2C19-predicted and pharmacokinetically verified CYP2C19 metabolic phenotypes in Native American cohorts. However, functional studies involving genotypic correlations with pharmacokinetic parameters are warranted to ascertain the importance of the CYP2C:TG haplotype.

Single Nucleotide Variants as Proxies for HLA-A*31:01 in Native American Populations.

Carbamazepine triggers dermatologic hypersensitivity reactions, associated with specific human leukocyte antigens (HLAs), especially HLA-B*15:02 and HLA-A*31:01. Previous efforts to identify single nucleotide variants (SNVs) with high predictive value as HLA proxies, revealed that rs1061235 and rs17179220 fulfill these requirements for HLA-A*31:01 in some but not all populations. Herein we explored the predictive performance of rs1061235 and rs17179220 as HLA-A*31:01 tags in populations of Native American ancestry, which are largely underrepresented in pharmacogenomic studies. The study cohorts comprised the overall Admixed American superpopulation of the 1000 Genomes Project (1 KG_AMR), a subcohort of individuals with predominant Native American ancestry (1 KG_NAT), the Native American population of the Human Genome Diversity Project (HGDP), plus Kaingang (KRC) and Guarani (GRC and GKW) adults from indigenous reservation areas in Brazil. The diversity of cohorts is reflected in the range of frequencies of HLA-A*31:01 (0.02-0.65), rs1061235 (0.03-0.13) and rs17179220 (0.12-0.66), as well as in the predictive performance of these SNVs as HLA-A*31:01 proxies. NPV (negative predictive value), the metric of primary interest for pharmacogenetic-informed carbamazepine prescription was maximal (NPV = 1.0) for both SNVs in 1 KG_AMR and 1 KG_NAT, for rs17179220, but not rs1061235 (NPV = 0.91) in HGDP, and for rs17179220 in GWK, but not GRC (NPV = 0.88) or KRC (NPV = 0.80). Collectively, the data support the notion that rs1061235 and rs17179220 are not optimal proxies for HLA-A*31:01 across populations of Native American ancestry.

Remarkably Low KIR and HLA Diversity in Amerindians Reveals Signatures of Strong Purifying Selection Shaping the Centromeric KIR Region.

The killer-cell immunoglobulin-like receptors (KIR) recognize human leukocyte antigen (HLA) molecules to regulate the cytotoxic and inflammatory responses of natural killer cells. KIR genes are encoded by a rapidly evolving gene family on chromosome 19 and present an unusual variation of presence and absence of genes and high allelic diversity. Although many studies have associated KIR polymorphism with susceptibility to several diseases over the last decades, the high-resolution allele-level haplotypes have only recently started to be described in populations. Here, we use a highly innovative custom next-generation sequencing method that provides a state-of-art characterization of KIR and HLA diversity in 706 individuals from eight unique South American populations: five Amerindian populations from Brazil (three Guarani and two Kaingang); one Amerindian population from Paraguay (Aché); and two urban populations from Southern Brazil (European and Japanese descendants from Curitiba). For the first time, we describe complete high-resolution KIR haplotypes in South American populations, exploring copy number, linkage disequilibrium, and KIR-HLA interactions. We show that all Amerindians analyzed to date exhibit the lowest numbers of KIR-HLA interactions among all described worldwide populations, and that 83-97% of their KIR-HLA interactions rely on a few HLA-C molecules. Using multiple approaches, we found signatures of strong purifying selection on the KIR centromeric region, which codes for the strongest NK cell educator receptors, possibly driven by the limited HLA diversity in these populations. Our study expands the current knowledge of KIR genetic diversity in populations to understand KIR-HLA coevolution and its impact on human health and survival.

How natural selection shapes genetic differentiation in the MHC region: A case study with Native Americans.

The Human Leukocyte Antigen (HLA) loci are extremely well documented targets of balancing selection, yet few studies have explored how selection affects population differentiation at these loci. In the present study we investigate genetic differentiation at HLA genes by comparing differentiation at microsatellites distributed genomewide to those in the MHC region. Our study uses a sample of 494 individuals from 30 human populations, 28 of which are Native Americans, all of whom were typed for genomewide and MHC region microsatellites. We find greater differentiation in the MHC than in the remainder of the genome (FST-MHC = 0.130 and FST-Genomic = 0.087), and use a permutation approach to show that this difference is statistically significant, and not accounted for by confounding factors. This finding lies in the opposite direction to the expectation that balancing selection reduces population differentiation. We interpret our findings as evidence that selection favors different sets of alleles in distinct localities, leading to increased differentiation. Thus, balancing selection at HLA genes simultaneously increases intra-population polymorphism and inter-population differentiation in Native Americans.

Demographic history and selection at HLA loci in Native Americans.

The American continent was the last to be occupied by modern humans, and native populations bear the marks of recent expansions, bottlenecks, natural selection, and population substructure. Here we investigate how this demographic history has shaped genetic variation at the strongly selected HLA loci. In order to disentangle the relative contributions of selection and demography process, we assembled a dataset with genome-wide microsatellites and HLA-A, -B, -C, and -DRB1 typing data for a set of 424 Native American individuals. We find that demographic history explains a sizeable fraction of HLA variation, both within and among populations. A striking feature of HLA variation in the Americas is the existence of alleles which are present in the continent but either absent or very rare elsewhere in the world. We show that this feature is consistent with demographic history (i.e., the combination of changes in population size associated with bottlenecks and subsequent population expansions). However, signatures of selection at HLA loci are still visible, with significant evidence selection at deeper timescales for most loci and populations, as well as population differentiation at HLA loci exceeding that seen at neutral markers.

Association between KIR genes and dust mite sensitization in a Brazilian population.

BACKGROUND: Killer cell immunoglobulin-like receptors (KIRs), found on the surface of natural killer (NK) cells, play a key role in controlling the innate response. Such response depends on a series of cellular interactions between these receptors and HLA activating/inhibiting ligands. Atopic diseases have been associated with genes that regulate cytokine production and HLA genes, which may either protect or predispose to hypersensitivity. OBJECTIVE: To verify an association study of KIR genes with sensitization to the following mites: Dermatophagoides farinae, Dermatophagoides pteronyssinus, and Blomia tropicalis. METHODS: A total of 341 children aged up to 14 years, were classified as mite-sensitive or mite-insensitive after undergoing a skin prick test for immediate allergic reactions. The presence/absence of KIR genes and their human leukocyte antigen (HLA) ligands was determined by polymerase chain reaction-sequence specific oligonucleotide (PCR-SSO) with the commercial kit LabType™ using Luminex™. RESULTS: The frequencies of KIR genes and their respective class I HLA ligands and the frequency of haplotypes were performed in sensitive and insensitive individuals, and no significant differences were found. CONCLUSION: Our results suggest no influence of KIR genes on resistance/susceptibility to sensitization to dust mites.

Association between HLA genes and dust mite sensitivity in a Brazilian population.

BACKGROUND: Type I hypersensitivity, also known as IgE-mediated allergy, is a complex, multifactorial condition whose onset and severity are influenced by both genetic and environmental factors. Mite allergens stimulate the production of humoral response (IgE), especially in children, which is closely involved in atopic asthma and rhinitis. OBJECTIVE: This study aimed to investigate the association between HLA class I (-A, -B, and -C), and HLA class II (-DRB1) genes in individuals sensitive to dust mites (Dermatophagoides farinae, Dermatophagoides pteronyssinus, or Blomia tropicalis) and mite-insensitive controls. METHODS: 396 participants were grouped as mite-sensitive and mite-insensitive according to immediate hypersensitivity as determined by skin-prick tests, and to HLA genotyping by polymerase chain reaction-sequence specific oligonucleotide (PCR-SSO). RESULTS: After chi-square heterogeneity testing no significant differences were observed in HLA-A, B, and C genes, except for the HLA-DRB1 locus, which, showed a negative association for DRB1∗04, between mite-sensitive and mite-insensitive individuals. In high resolution, DRB1∗04:11 allele was significantly different from all other results (P=0.0042, OR=0.26, and 95%CI=0.09-0.70). The analysis stratified by etiologic agent confirmed these associations. CONCLUSION: Our results suggest a possible association between HLA-DRB1 genes and hypersensitivity to dust mites.

Variability of innate immune system genes in Native American populations-relationship with history and epidemiology.

OBJECTIVES: The immune system of a host, defending him/her against invading pathogens, has two main subsystems: innate immunity and acquired immunity. There are several evidences showing that Native American populations are immunologically different from non-Native populations. Our aim was to describe the variability of innate immune system genes in Native American populations. MATERIALS AND METHODS: We investigated heterozygozities and patterns of population differentiation (FST ) of 14 polymorphisms related to the innate immune response in five Native American populations (Aché, Guarani-Kaiowá, Guarani-Ñandeva, Kaingang, and Xavante) and the results were compared with the three major world population data (YRI, CEU, and CHB) available at the 1,000 genomes database. RESULTS: Mean heterozygosities ranged between 0.241 ± 0.057 (Aché) and 0.343 ± 0.033 (Kaingang), but no significant differences were observed (Friedman test, P = 0.197). Mean heterozygosities were also not significantly different when Amerindians were pooled and compared with the 1000 genomes populations (Friedman test, P = 0.506). When the Native American populations were grouped as Amerindians, a significantly higher FST value (0.194) was observed between the Amerindian and African populations. The Ewens-Watterson neutrality test showed that these markers are not under strong selective pressure. DISCUSSION: Native American populations present similar levels of heterozygosity as those of other continents, but are different from Africans in the frequency of polymorphisms of innate immune genes. This higher differentiation is probably due to demographic processes that occurred during the out-of-Africa event.

Rio Grande do Norte, Brazil, voluntary bone marrow donors registry analysis.

OBJECTIVE: this study aimed to report the allele and haplotype frequencies of volunteer bone marrow donors (VBMD) from the state of Rio Grande do Norte (RN) who were enrolled in the Brazilian Volunteer Bone Marrow Donor Registry (REDOME). METHODS: the sample comprised 12,973 VBMD who had their allele and haplotype frequencies calculated by Arlequin 3.5.1.2. A multivariate analysis of the data was obtained through a principal component analysis (PCA) and hierarchical cluster analysis (HCA) performed with SPSS 8.0. RESULTS: the most frequent allelic group was HLA-A*02, followed by -DRB1*13, -DRB1*04, -DRB1*07, -B*44, -B*35, -A*24 and -DRB1*01. Of the 2,701 haplotypes observed, the three most frequent were HLA-A*01 B*08 DRB1*03 (1.62%), -A*29 B*44 DRB1*07 (1.56%) and -A*02 B*44 DRB1*04 (1.29%). These haplotypes were in linkage disequilibrium. RN allele and haplotype frequencies were very similar to those in other Brazilian states in which similar studies have been performed. The PCA revealed that RN is highly genetically similar to Caucasian populations, especially those from Iberian countries, which strongly influenced the state's ethnic composition. Africans and Amerindians also influenced the RN population structure, to a lesser extent. CONCLUSION: the HCA reinforced the conclusion that, despite its highly admixed profile, the RN population is genetically similar to European and European-descended populations. The PCA also showed that RN cities do not contribute to the same extent to REDOME, with less populous cities being underrepresented, indicating the need to enroll more VBMD from these smaller cities to faithfully depict the state's population structure in the database.

Rio Grande do Norte, Brazil, voluntary bone marrow donors registry analysis / Análise do registro de doadores voluntários de medula óssea do Rio Grande do Norte, Brasil.

Objective: this study aimed to report the allele and haplotype frequencies of volunteer bone marrow donors (VBMD) from the state of Rio Grande do Norte (RN) who were enrolled in the Brazilian Volunteer Bone Marrow Donor Registry (REDOME). Methods: the sample comprised 12,973 VBMD who had their allele and haplotype frequencies calculated by Arlequin 3.5.1.2. A multivariate analysis of the data was obtained through a principal component analysis (PCA) and hierarchical cluster analysis (HCA) performed with SPSS 8.0. Results: the most frequent allelic group was HLA-A*02, followed by -DRB1*13, -DRB1*04, -DRB1*07, -B*44, -B*35, -A*24 and -DRB1*01. Of the 2,701 haplotypes observed, the three most frequent were HLA-A*01 B*08 DRB1*03 (1.62%), -A*29 B*44 DRB1*07 (1.56%) and -A*02 B*44 DRB1*04 (1.29%). These haplotypes were in linkage disequilibrium. RN allele and haplotype frequencies were very similar to those in other Brazilian states in which similar studies have been performed. The PCA revealed that RN is highly genetically similar to Caucasian populations, especially those from Iberian countries, which strongly influenced the state’s ethnic composition. Africans and Amerindians also influenced the RN population structure, to a lesser extent. Conclusion: the HCA reinforced the conclusion that, despite its highly admixed profile, the RN population is genetically similar to European and European-descended populations. The PCA also showed that RN cities do not contribute to the same extent to REDOME, with less populous cities being underrepresented, indicating the need to enroll more VBMD from these smaller cities to faithfully depict the state’s population structure in the database. .

Objetivo: relatar as frequências alélicas e haplotípicas do HLA-A, -B e -DRB1 de doadores voluntários de medula óssea (DVMO) do Rio Grande do Norte (RN), inscritos no Registro Nacional de Doadores de Medula Óssea (REDOME). Metodologia: 12.973 DVMO tiveram suas frequências alélica e haplotípica calculadas pelo programa Arlequin 3.5.1.2. Uma análise multivariada dos dados foi obtida por meio da Análise de Componente Principal (ACP) e da Análise de Cluster Hierárquico (ACH) realizadas pelo SPSS 8.0. Resultados: os grupos alélicos mais frequentes foram HLA-A*02, seguido por -DRB1*13, -DRB1*04, -DRB1*07, -B*44, -B*35, -A*24 e -DRB1*01. Dos 2.701 haplótipos observados, os três mais frequentes foram HLA-A*01 B*08 DRB1*03 (1,62%), -A*29 B*44 DRB1*07 (1,56%) e -A*02 B*44 DRB1*04 (1,29%), que se encontravam em desequilíbrio de ligação. As frequências alélicas e haplotípicas do RN são bastante similares às de outros estados brasileiros em que trabalhos semelhantes foram executados. A ACP revelou ser o RN geneticamente muito semelhante a populações caucasianas, especialmente a dos países ibéricos, os quais influenciaram fortemente na composição étnica do Estado. Africanos e ameríndios também contribuíram para a estrutura populacional, mas em menor proporção. Conclusão: a ACH reforçou a conclusão de que, apesar de seu perfil miscigenado, a população do RN se assemelha geneticamente com populações europeias e que descendem das europeias. A ACP também mostrou que as cidades do RN não contribuem equitativamente na composição do REDOME, de modo que cidades pouco populosas estão sub-representadas, apontando a necessidade de cadastrar mais DVMO dessas cidades para que a estrutura da população seja fielmente retratada. .

Association of cytokines in individuals sensitive and insensitive to dust mites in a Brazilian population.

INTRODUCTION: Allergic reaction to dust mites is a relatively common condition among children, triggering cutaneous and respiratory responses that have a great impact on the health of this population. Anaphylactic hypersensitivity is characterized by an exacerbated response involving the production of regulatory cytokines responsible for stimulating the production of IgE antibodies. OBJECTIVE: To investigate an association of variants in cytokine genes (IL1A-889, IL1B-511, +3962, IL1R1970, IL1RA11100, IL4RA+1902, IL12-1188, IFNG+874, TGFB1 codon 10, codon 25, TNFA-308, -238, IL2-330, +166, IL4-1098, -590, -33, IL6-174, nt565, and IL10-1082, -819, -592) between patients sensitive to dust mites and a control group. METHODS: A total of 254 patients were grouped as atopic and non-atopic according to sensitivity as evaluated by the Prick Test and to cytokine genotyping by the polymerase chain reaction-sequence specific primers (PCR-SSP) method using the Cytokine Genotyping Kit. RESULTS: A comparison between individuals allergic to Dermatophagoides farinae, Dermatophagoides pteronyssinus, and Blomia tropicalis and a non-atopic control group showed significant differences between allele and genotype frequencies in the regulatory regions of cytokine genes, with important evidence for IL4-590 in T/C (10.2% vs. 43.1%, odd ratio [OR] = 0.15, p = 5.2 10-8, pc = 0.0000011, and 95% confidence interval [95%CI] = 0.07-0.32) and T/T genotypes (42.9% vs. 13.8%, OR = 4.69, p = 2.5 10-6, pc = 0.000055, and 95%CI = 2.42-9.09). Other associations were observed in the pro-inflammatory cytokines IL1A-889 (T/T, C, and T) and IL2-330 (G/T and T/T) and the anti-inflammatory cytokines IL4RA+1902 (A and G), IL4-590 (T/C, T/T, C, and T), and IL10-592 (A/A, C/A, A, and C). CONCLUSION: Our results suggest a possible association between single nucleotide polymorphisms (SNPs) in cytokine genes and hypersensitivity to dust mites.

[Autosomal dominant polycystic kidney disease in hemodialysis patients in Southern Brazil]. / Doenca renal policistica autossomica dominante em pacientes em hemodialise no sul do Brasil.

INTRODUCTION: Autosomal dominant polycystic kidney disease is the most common hereditary renal disease in humans. OBJECTIVE: To examine the prevalence, clinical and laboratory characteristics of patients with polycystic kidneys and relate disease manifestations by gender. METHODS: This was an observational and retrospective study. All the medical records of patients with polycystic kidneys who initiated hemodialysis between 1995 and 2012, in four centers that treat patients of the coverage area of the 15th regional health Paraná (Brazil), were analyzed. RESULTS: The study included 48 patients with polycystic kidneys, the primary cause of stage 5 CKD. Disease prevalence was one in 10,912 people. The average age of dialysis initiation was 50.7 years and the follow-up time on dialysis until transplantation (36.5 months) was lower among men. Hypertension was the most frequent diagnosis in 73% of patients, predominantly in women (51.4%). The liver cyst was the most frequent extrarenal manifestations in men (60.0%). The death occurred in 10.4% of patients using hemodialysis, and 60% of men. The class of antihypertensive drug used was that acts on the renin-angiotensin system with higher frequency of use among women (53.3%). The post-dialysis urea was significantly higher in men. CONCLUSION: The prevalence of the disease is low among hemodialysis patients in southern Brazil. The differences observed between genders, with the exception of the post-dialysis urea, were not significant. The findings are different from those reported in North America and Europe.

Doenca renal policistica autossomica dominante em pacientes em hemodialise no sul do Brasil / Autosomal dominant polycystic kidney disease in hemodialysis patients in southern Brazil

Introdução: A doença renal policística autossômica dominante é a enfermidade renal hereditária mais comum em seres humanos. Objetivo: Analisar a prevalência, características clínicas e laboratoriais de pacientes com rins policísticos e relacionar as manifestações da doença por gênero. Métodos: Trata-se de um estudo observacional e retrospectivo. Foram revisados todos os prontuários médicos de pacientes com rins policísticos admitidos para hemodiálise entre 1995 e 2012, em quatro centros que atendem a área de abrangência da 15ª regional de saúde do Paraná, Brasil. Resultados: Fizeram parte do estudo 48 pacientes com rins policísticos, causa primária da doença renal crônica (DRC) estágio 5. A prevalência da doença foi de um em 10.912 habitantes. A média de idade de ingresso na hemodiálise (50,7 anos) e o tempo de seguimento em hemodiálise até o transplante (36,5 meses) foi menor nos homens. A hipertensão arterial foi o diagnóstico mais frequente em 73% dos pacientes, com predominância em mulheres (51,4%). O cisto hepático foi a manifestação extrarrenal mais frequente nos homens (60,0%). Foram a óbito 10,4% dos pacientes que faziam uso de hemodiálise, sendo 60% de homens. A classe de droga anti-hipertensiva mais utilizada foi a que atua no sistema renina-angiotensina, com maior frequência de uso nas mulheres (53,3%). A ureia pós-diálise foi significativamente maior em homens. Conclusão: A prevalência da doença é baixa entre pacientes em hemodiálise no sul do Brasil. As diferenças observadas entre os gêneros, com exceção da ureia pós, não foram significantes. Os dados encontrados são diferentes dos reportados na América do Norte e Europa. .

Introduction: Autosomal dominant polycystic kidney disease is the most common hereditary renal disease in humans. Objective: To examine the prevalence, clinical and laboratory characteristics of patients with polycystic kidneys and relate disease manifestations by gender. Methods: This was an observational and retrospective study. All the medical records of patients with polycystic kidneys who initiated hemodialysis between 1995 and 2012, in four centers that treat patients of the coverage area of the 15th regional health Paraná (Brazil), were analyzed. Results: The study included 48 patients with polycystic kidneys, the primary cause of stage 5 CKD. Disease prevalence was one in 10,912 people. The average age of dialysis initiation was 50.7 years and the follow-up time on dialysis until transplantation (36.5 months) was lower among men. Hypertension was the most frequent diagnosis in 73% of patients, predominantly in women (51.4%). The liver cyst was the most frequent extrarenal manifestations in men (60.0%). The death occurred in 10.4% of patients using hemodialysis, and 60% of men. The class of antihypertensive drug used was that acts on the renin-angiotensin system with higher frequency of use among women (53.3%). The post-dialysis urea was significantly higher in men. Conclusion: The prevalence of the disease is low among hemodialysis patients in southern Brazil. The differences observed between genders, with the exception of the post-dialysis urea, were not significant. The findings are different from those reported in North America and Europe. .

Características sociodemográficas e aspectos clínicos de pacientes com doença renal policística do adulto submetidos à hemodiálise / Sociodemographic characteristics and clinical features of patients withadult polycystic kidney disease undergoing hemodialysis

Objetivos: Analisar as características sociodemográficas e clínicas de pacientes portadores da doença renal policística do adulto admitidos nos serviços de hemodiálise no noroeste do estado do Paraná.Métodos: Trata-se de um estudo observacional, descritivo e retrospectivo. Foram revisados os prontuários de pacientes com rins policísticos admitidos para hemodiálise entre 1995 e 2012, em quatro centros que atendem pacientes da área de abrangência da 15ª Regional de Saúde do Paraná.Resultados: Observou-se que 10,3% dos pacientes em hemodiálise tinham rins policísticos como principal causa de doença renal crônica estágio 5. A idade média dos pacientes foi de 54,9±9,4 anos (variando entre 27 e 74 anos), com distribuição igual entre os sexos e predominância caucasiana (72,9%). A idade média de ingresso na hemodiálise foi de 50±10,2 anos. A manifestação clínica associada mais comum foi a hipertensão arterial sistêmica (66,7%). Cisto hepático foi a principal manifestação extrarrenal (10,4%). Vinte e cinco por cento dos pacientes evoluíram para transplante renal e 22,9% foram submetidos à nefrectomia. As classes de drogas anti-hipertensivas mais amplamente usadas foram os ?-bloqueadores (41,7%) e as drogas que diminuem a atividade do sistema renina-angiotensina (31,3%), enquanto 56,3% dos pacientes fizeram uso de eritropoetina humana recombinante.Conclusões: Este estudo epidemiológico foi pioneiro na região noroeste do Paraná. Encontrou-se, na população estudada, um perfil sociodemográfico e clínico da doença renal policística do adulto semelhante ao da América do Norte e Europa, provavelmente pela constituição étnica da amostragem ser predominantemente de euro-descendentes.

Aims: To analyze the socio-demographic and clinical characteristics of patients with adult polycystic kidney disease admitted to hemodialysis services in Northwestern Paraná state, Brazil. Methods: This was an observational, descriptive and retrospective longitudinal study. Medical records of patients with polycystic kidneys who initiated hemodialysis between 1995 and 2012, in four centers that treat patients of the coverage area of the 15th Regional Health Region of Paraná stat e where analyzed. Results: We found that 10.3% of hemodialysis patients had polycystic kidney disease as a leading cause of stage 5 of chronic kidney disease. The mean age of patients was 54.9±9.4 years (ranging between 27 and 74 years), with equal gender distribution and Caucasian predominance (72.9%). The average age of dialysis initiation was 50±10.2 years. The most common comorbidity was systemic hypertension (66.7%). Liver cyst was the main extra-renal manifestation (10.4%). Twenty-five percent of the patients required renal transplantation, and (22.9%) undergone nephrectomy. The most widely used classes of antihypertensive drugs were β -blockers (41.7%) and drugs that act on the renin-angiotensin system (31.3%), while 56.3% of patients were treated with recombinant human erythropoietin. Conclusions: This is a pioneering epidemiological study in Northwestern Paraná state. We found in this population a sociodemographic and clinical profile of adult polycystic kidney disease similar to that of North America and Europe, probably because the ethnic constitution of the sample was predominantly of Euro-descendants.

KIR gene content in amerindians indicates influence of demographic factors.

Although the KIR gene content polymorphism has been studied worldwide, only a few isolated or Amerindian populations have been analyzed. This extremely diverse gene family codifies receptors that are expressed mainly in NK cells and bind HLA class I molecules. KIR-HLA combinations have been associated to several diseases and population studies are important to comprehend their evolution and their role in immunity. Here we analyzed, by PCR-SSP (specific sequencing priming), 327 individuals from four isolated groups of two of the most important Brazilian Amerindian populations: Kaingang and Guarani. The pattern of KIR diversity among these and other ten Amerindian populations disclosed a wide range of variation for both KIR haplotypes and gene frequencies, indicating that demographic factors, such as bottleneck and founder effects, were the most important evolutionary factors in shaping the KIR polymorphism in these populations.

Stability or variation? Patterns of lactase gene and its enhancer region distributions in Brazilian Amerindians.

Lactase persistence (LP) is the phenotypic trait in which lactase secretion is maintained during adulthood. LP is due to mutations in the LCT enhancer region, located 14-kb upstream of the gene. In Europeans, the -13910*T allele is associated with LP. In Africans this allele is rare while other mutations in this same region were related to LP. The LCT is highly polymorphic in human populations, but so far Brazilian Amerindians had not been investigated for these polymorphisms or for the presence of LP mutations. We describe the genetic diversity of the LCT region and the presence of LP enhancer mutations in four native Brazilian populations (Guarani-Kaiowá, Guarani-Ñandeva, Kaingang, and Xavante). Twelve polymorphisms were genotyped by PCR-based methods. The -13910*T allele varied from 0.5% in the Xavante to 7.6% in the Guarani-Ñandeva. These frequencies probably derive from European sources and they correlate with non-native admixture proportions previously estimated for these groups. But since admixture is virtually absent in the Xavante, we suggest that the presence of the LP allele could have been determined by a de novo mutation. No other mutations in the -14 kb enhancer region were found. The LCT was highly polymorphic in the present sample showing 15 haplotypes with a heterogeneous distribution among the four Amerindian populations. This diversity could be due to drift, as indicated by the neutrality test performed.

CD80 and CD86 polymorphisms in populations of various ancestries: 5 new CD80 promoter alleles.

CD80 and CD86 are closely linked genes on chromosome 3 that code for glycoproteins of the immunoglobulin superfamily, expressed on the surface of antigen-presenting cells. These costimulatory molecules play essential roles for stimulation and inhibition of T cells through binding to CD28 and CTLA-4 receptors. In this study, CD80 promoter and CD86 exon 8 polymorphisms were analyzed to investigate the genetic diversity and microevolution of the 2 genes. We genotyped 1,124 individuals, including Brazilians of predominantly European, mixed African and European, and Japanese ancestry, 5 Amerindian populations, and an African sample. All variants were observed in Africans, which suggests their origin in Africa before the human migrations out of that continent. Five new CD80 promoter alleles were identified and confirmed by cloning and sequencing, and promoter 2 is most likely the ancestral allele. Nucleotide -79 is monomorphic in 4 Amerindian populations, where the presence of the -79 G allele is probably the result of gene flow from non-Amerindians.

Class-I human leukocyte alleles in leprosy patients from Southern Brazil.

INTRODUCTION: The present study was designed to investigate a possible role of HLA (histocompatibility leucocyte antigen) class-I alleles (HLA-A, -B, and -C) in leprosy patients from Southern Brazil. METHODS: Two hundred and twenty-five patients with leprosy and 450 individuals for the control group were involved in this research. HLA genotyping was performed through PCR-SSO protocols (One Lambda, USA); the frequency of these alleles was calculated in each group by direct counting, and the frequencies were then compared. RESULTS: There was an association between HLA-A*11 (6.9% vs 4.1%, p=0.0345, OR=1.72, 95% CI=1.05-2.81), HLA-B*38 (2.7% vs. 1.1%, p=0.0402, OR=2.44, 95% CI=1.05-5.69), HLA-C*12 (9.4% vs. 5.4%, p=0.01, OR=1.82, 95% CI=1.17-2.82), and HLA-C*16 (3.1% vs. 6.5%, p=0.0124, OR=0.47, 95% CI=0.26-0.85) and leprosy per se. In addition, HLA-B*35, HLA-C*04, and HLA-C*07 frequencies were different between lepromatous (LL) and tuberculoid (TT) patients. However, after adjusting for the number of alleles compared, Pc values became nonsignificant. CONCLUSIONS: Although our results do not support the previous findings that HLA class-I alleles play a role in leprosy pathogenesis, we suggest new studies because of the importance of the association between the HLA and KIR in the innate immune response to leprosy.

Class-I human leukocyte alleles in leprosy patients from Southern Brazil / Alelos leucocitários humanos em pacientes com hanseníase do sul do Brasil

INTRODUCTION: The present study was designed to investigate a possible role of HLA (histocompatibility leucocyte antigen) class-I alleles (HLA-A, -B, and -C) in leprosy patients from Southern Brazil. METHODS: Two hundred and twenty-five patients with leprosy and 450 individuals for the control group were involved in this research. HLA genotyping was performed through PCR-SSO protocols (One Lambda, USA); the frequency of these alleles was calculated in each group by direct counting, and the frequencies were then compared. RESULTS: There was an association between HLA-A*11 (6.9 percent vs 4.1 percent, p=0.0345, OR=1.72, 95 percent CI=1.05-2.81), HLA-B*38 (2.7 percent vs. 1.1 percent, p=0.0402, OR=2.44, 95 percent CI=1.05-5.69), HLA-C*12 (9.4 percent vs. 5.4 percent, p=0.01, OR=1.82, 95 percent CI=1.17-2.82), and HLA-C*16 (3.1 percent vs. 6.5 percent, p=0.0124, OR=0.47, 95 percent CI=0.26-0.85) and leprosy per se. In addition, HLA-B*35, HLA-C*04, and HLA-C*07 frequencies were different between lepromatous (LL) and tuberculoid (TT) patients. However, after adjusting for the number of alleles compared, Pc values became nonsignificant. CONCLUSIONS: Although our results do not support the previous findings that HLA class-I alleles play a role in leprosy pathogenesis, we suggest new studies because of the importance of the association between the HLA and KIR in the innate immune response to leprosy.

INTRODUÇÃO: O presente estudo foi desenhado para investigar um possível papel para os alelos HLA (histocompatibility leucocyte antigen) de classe I (HLA-A, -B, and -C) em pacientes com hanseníase do sul do Brasil. MÉTODOS: Duzentos e vinte e cinco pacientes com hanseníase e 450 indivíduos para o grupo-controle foram envolvidos nesse estudo. O genótipo HLA foi determinado por protocolos PCR-SSO (One Lambda, USA) e, a frequência desses alelos foi calculada em cada grupo por contagem direta e, após, comparadas. RESULTADOS: Houve associação entre HLA-A*11 (6,9 por cento vs 4,1 por cento; p = 0,0345; OR = 1,72; CI = 1,05 - 2,81), HLA-B*38 (2,7 por cento vs 1,1; p = 0,0402; OR = 2,44; CI 95 por cento = 1,05-5,69), HLA-C*12 (9,4 por cento vs 5,4 por cento; p = 0,01; OR = 1,82; CI 95 por cento = 1,17-2,82) e HLA-C*16 (3,1 vs 6,5 por cento; p = 0,0124; OR = 0,47; CI 95 por cento = 0,26-0,85) e hanseníase per se. Além disso, as frequências de HLA-B*35, HLA-C*04 e HLA-C*07 foram diferentes entre os pacientes com as formas lepromatosa (LL) e tuberculoide (TT). Contudo, após o ajuste para o número de alelos comparados, os valores de p se tornaram não significativos. CONCLUSÕES: Embora nossos resultados não sustentem as conclusões anteriores de que os alelos HLA de classe I desempenham um papel na associação com a patogênese da hanseníase, sugerimos novos estudos devido à importância da associação entre HLA e KIR na resposta imune inata à hanseníase.

Contrasting patterns of nuclear and mtDNA diversity in Native American populations.

We report an integrated analysis of nuclear (autosomal, X- and Y-chromosome) short tandem repeat (STR) data and mtDNA D-loop sequences obtained in the same set of 22 Native populations from across the Americas. A north to south gradient of decreasing population diversity was observed, in agreement with a settlement of the Americas from the extreme northwest of the continent. This correlation is stronger with "least cost distances," which consider the coasts as facilitators of migration. Continent-wide estimates of population structure are highest for the Y-chromosome and lowest for the autosomes, consistent with the effective size of the different marker systems examined. Population differentiation is highest in East South America and lowest in Meso America and the Andean region. Regional analyses suggest a deviation from mutation-drift equilibrium consistent with population expansion in Meso America and the Andes and population contraction in Northwest and East South America. These data hint at an early divergence of Andean and non-Andean South Americans and at a contrasting demographic history for populations from these regions.